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http://www.psychiatrictimes.com/bipolar-
Patients With Bipolar and Unipolar Depression Show Similar Response to Electroconvulsive Therapy - P
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Psychiatric Times is the most widely read publication in the field of psychiatry. The Web site features outstanding columnists, compelling features, vital clinical news, intriguing special reports, career opportunities and the chance to earn Category 1 credit.
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The FDA today issued a new set of warnings for the non-stimulant ADHD drug Strattera, made by Eli Lilly. I'll just quote the FDA's new language: Severe Liver
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http://www.examiner.com/x-10560-Special-
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According to a recent press release, a new study found that there is a genetic variation behind the troubles children with pediatric bipolar disorder may face with his or her body clock. The circadian rhythm is used to regulate sleep. ...
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http://www.healthcentral.com/bipolar/c/1
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One of the tragedies of our illness is how it rips apart our families. Check out the various posts and questions and comments from readers on this site and you ...
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CONTEXT AND SUMMARY OF JBRF SPONSORED RESEARCH
Why Define a New Phenotype?
The Quest for Homogeneity
It
has become apparent to many psychiatric researchers that the manner in
which most mental disorders have been defined since the early 1980’s
may not be so helpful in our quest to explore... and understand their
biological roots. Current diagnostic definitions, conceived of under
the assumption that there are strict boundaries between disorders,
attempt to pare down an illness to include only those symptoms thought
to be most directly related to it. This approach excludes a symptom
from a diagnostic definition if it could be considered more directly
relevant to an alternate illness. Hence, in this scenario, the
definition of bipolar disorder is primarily shaped by symptoms of mania
and depression. The anxiety, aggression, obsessive-compulsive behaviors
and other symptoms which so often accompany a bipolar condition are
cleaved off and assigned to different diagnostic groupings. The
approach is called “categorical” because it attempts to separate
symptoms into discreet categories.
Psychiatry has been using these classifications for the past 30
years and they have been very helpful in the standardization of
diagnoses. However, the process that created these diagnostic
definitions was not derived from scientific evidence. Rather it was
diagnosis-by-consensus based upon the best clinical knowledge available
at the time. Regardless of how enduring or universally accepted these
diagnostic constructs have become, they were always meant to be changed
based on new research findings.
Necessarily relying upon categorical classifications to gather study
subjects, genetic and neuroimaging studies have had limited success in
finding the causes that underlie complex mental disorders such as
bipolar disorder. Although research subjects may share the same
diagnoses, it seems that categorically constructed diagnoses may not be
a useful guide to identify those individuals who share similar genetic
or neurophysiological characteristics. This may account for the lack of
meaningful results that has subsequently stalled efforts to find more
targeted treatments.
In response, investigators are beginning to conceptualize mental
disorders in a new way. This new approach rejects the previous
categorization of exclusive symptoms. Instead, it accepts the
inevitable overlap of symptoms between disorders. Further, it
quantifies the relevance of those symptoms based on degrees of severity
and heritability.
Under this construct, mental illness is regarded as a matrix of
behavioral and/or functional “dimensions” each made up of a particular
cluster of symptoms. This conceptualization is called a “dimensional”
approach. Drs. Kendell and Jablensky have written an article that
explains dimensional analysis more fully: Distinguishing Between the
Validity and Utility of Psychiatric Diagnoses. American Journal of
Psychiatry 2003; 160:4-12. http://ajp.psychiatryonline.org/cgi/repr
While multiple dimensions of clustered symptoms may seem to cast a
wide and loose diagnostic net, the combined orchestration of symptoms
actually provides much more specific criteria than traditional
diagnostic definitions. Further, the sets of traits that they identify
are more developmentally predictable than the stripped down symptom
lists of categorical definitions.
The clearer, more refined description afforded by the dimensional
analysis increases the chances of gathering a pool of individuals who
are genetically similar. By even further dissecting that profile into
subgroups based on the heritability of certain traits, the chances for
identifying a homogeneous study population are greatly enhanced.
In genomics, the importance of analyzing symptom dimensions as a
strategy for genotyping is becoming more evident. For a genome-wide
linkage scan in a large sample of bipolar adults, Cheng et al. (2006)
used both standard diagnostic models and the comorbid symptoms of
psychosis, suicidal behavior and panic disorder to identify phenotypic
subtypes. Over half the regions implicated by the strongest linkage
signals (genome-wide significance) were identified by the phenotypic
subtypes. Cheng and colleagues concluded that a dissection of the
disease phenotype can enrich the harvest of linkage signals and
expedite the search for susceptibility genes.1
In neuroimaging studies of children with obsessive-compulsive
disorder (OCD), researchers broke down the subject pool by
distinguishable traits such as washing and checking. By doing so, they
were able to visualize specific neural circuits that identified those
discrete features. This clear association with a biological correlate
would have been obscured if they had used the diagnostic nomenclature
of DSM-IV.2
Not only may a dimensional analysis provide a more accurate route
for defining homogenous behavioral subtypes, but the landscape of
symptom-clusters that it reveals may more readily suggest particular
biological correlates. The identification of that correlate is
advantageous for two reasons. First, it provides a context and focus of
inquiry that may be new and revealing and which could suggest novel
therapeutic approaches. Second, it could lead to the identification of
quantifiable, distinguishing biological markers that could guide
differential diagnosis.
There is really no codified road map to help determine the
‘dimensional matrix’ of an illness. Indeed, the quantification of
unwieldy behavioral dimensions has deterred this line of thinking in
the past. However, rigorous statistical methods are now available that
can sort and quantify data; clustering together those symptoms that
significantly associate with one another. It is these clustered
symptoms, technically referred to as factors, that suggest a
“dimension” of behavior or functionality. Each factor is named
according to what its particular mix of symptoms suggests. Some
examples of factor names would be “sensory sensitivity”, “territorial
aggression” or “sleep/arousal”. Looking at the factors that are found
to be the most significant can provide an alternative, and perhaps even
more clinically relevant, view of the characteristics that are most
important in a disorder. This may lead to novel insights and new
research that prompt further dimensional refinements of the behavioral
subtype. This is the process which Dr. Demitri Papolos and an
interdisciplinary group of researchers from around the country have
pursued to arrive at their Fear of Harm phenotype of juvenile-onset
bipolar disorder.
The Fear Of Harm PhenotypeA More Highly Refined Slice of the Illness
Summary
For more than a decade, Dr. Papolos and his colleagues have sought
to gain a clearer understanding of juvenile bipolar disorder. Given the
terrible lack of consensus in the psychiatric community regarding the
diagnosis of this condition, these researchers elected to use a
dimensional approach to explore the conundrum and hopefully to provide
a better characterization of the illness. Indeed their work has allowed
them to conclude that, in addition to depression and mania, a variety
of other symptoms are part and parcel of the illness and that some of
those symptoms may actually eclipse mania and depression for diagnostic
and genetic relevance.
While their studies demonstrate that a very large majority of
children who had been diagnosed in the community, or were at risk for
juvenile bipolar disorder, are indeed significantly impaired,
investigators were able to define a subgroup of children who are at
greatest risk for the most severe form of this manic/depressive
syndrome. They call this subgroup the “Fear of Harm” (FOH) phenotype.
In addition to the high risk of self injury, injury to others and
suicide threat that are important characteristics of this phenotype,
children in this group also experience an early age of onset, severe
manic and depressive symptoms, early and frequent psychiatric
hospitalizations, significant social impairment and school problems.
Fortunately, the same questionnaires that were instrumental in
identifying this high risk group can easily be used within a community
setting to screen for children who fall into this category. Six factors
derived from the symptom list of the CBQ (Child Bipolar Questionnaire;
a screening tool which will be described below), can identify this
phenotype with 96% accuracy. As we all know, early detection greatly
improves a child’s outcome by setting into motion early intervention.
Beyond the clinical significance of the phenotype, it also has great
research potential. The strong heritability of its defining dimension
makes it an excellent candidate for a genetic inquiry. The ability of
the CBQ to accurately, easily and rapidly identify FOH subjects
increases the likelihood that a large, homogenous pool of DNA can be
gathered, thereby increasing the chances for a reproducible genetic
study.
What’s more, the dimensions that have been identified suggest a
neurobiological model of the illness. That model includes a
physiological marker and has led to the hypothesis that the orexigenic
neuropeptide circuit, a circuit that modulates arousal, sleep onset and
offset, REM propensity, appetite, fear sensitization, reward,
territorial aggression and body temperature rhythms, may be the
underlying biological correlate of the phenotype.
This potentially important phenotype, defined by the Fear of Harm
behavioral dimension, consists of symptoms that currently reside in
numerous diagnostic categories of the DSM-IV. These include
parasomnias, obsessive-compulsive and REM sleep behavior disorder,
bulimia, anorexia, suicidality and psychosis. FOH sets a new frame
around a specific set of highly heritable symptoms and so does not
pertain to any specific set of current DSM IV criteria and cannot be
diagnosed using accepted nomenclature.
How It Was Done: Data Collection
The JBRF (Juvenile Bipolar Research Foundation) website has served
as a portal for the collection of data on early-onset bipolar disorder.
Primarily, information comes in through the submissions of the CBQ. The
CBQ was developed to gather a broad range of symptom information about
children who were suspect for, or had received a community diagnosis
of, a bipolar disorder. The questionnaire asks parents to endorse
symptoms from a list of items that, while inclusive of mania and
depression, also lists symptoms from a variety of pediatric psychiatric
illnesses that are often considered co-morbid with juvenile bipolar
disorder (separation anxiety disorder, generalized anxiety disorder,
OCD, ODD, CD, and ADHD).
Reliable algorithms were developed that could comb through the data
and provide preliminarily identification of subjects with 1.) bipolar
disorder according to a DSM IV bipolar diagnosis as well as according
to various proposed phenotypes, 2.) bipolar disorder with and without
comorbid ADHD, and 3.) ADHD with no bipolar disorder. Thus a rapid and
flexible scoring system was created that could go through large
submissions of data and designate appropriate study groups. Using this
screening tool, investigators were able to use over 6,000 profiles for
their research. This treasure trove of information continues to grow
and provide the robust pools of data needed in order to be able to
conduct meaningful analyses.
Investigators also collected through the JBRF website, data from
YBOCS (the Yale Brown Obsessive Compulsive Scale) and OAS (the Overt
Aggression Scale). These well validated screening tools measure
anxiety, obsessive-compulsive behaviors and thoughts as well as
aggression directed towards self and others. The investigators gathered
this information to address the long expressed concern regarding the
high incidence of anxiety and aggression amongst these children. The
sample size for all studies was in the thousands of subjects.
How It Was Done: Studies
Investigators made the first important foothold on what would
develop into their highly refined subtype of the illness through the
use of data from YBOCS and OAS. Examining six items from YBOCS and two
items from OAS, they were able to demonstrate a relationship between
anxiety and aggression. They found that children with bipolar disorder
who were obsessively fearful that harm would come to themselves or
others were 2.7 times more likely to inflict serious harm on
themselves, and 8 times more likely to inflict serious harm on others,
than children from the same group who did not experience obsessive
fears. Investigators called this behavioral trait “Fear of Harm”, or
FOH, and the eight items that define it the “FOH index”. They further
found that children characterized by FOH were more likely to threaten
suicide than those who weren’t. This trait was determined not to be
found in healthy subjects. Investigators recognized FOH to be not only
an alarming behavioral dimension, but also a strong candidate for a
defining feature of a unique form of the disorder. (For the full
article, click here.)
Concurrent to the FOH study, investigators conducted a dimensional
analysis on the symptoms endorsed in almost 3,000 CBQ’s of children at
risk for, or who had received a community diagnosis of, bipolar
disorder. The study resulted in the clustering of symptoms into ten
behavioral dimensions or “factors”. While the familiar traits of
depression and mania were identified, it also clustered a factor which
combined symptoms of anxiety and aggression. The appearance of this
factor lent support to the FOH relationship from the YBOCS/OAS study.
Additionally, the analysis arrived at factors suggestive of behavioral
dimensions never before associated with the profile. Amongst those
factors are sleep cycle problems, sensory sensitivity and
oppositional/poor frustration tolerance; features that many parents of
children with bipolar disorder can tell you are inseparable from their
daily struggle.
Armed with a better dimensional understanding of the illness that
these two studies provided, investigators were ready to suggest an
alternative phenotype that they felt better defined juvenile bipolar
disorder. Central to the criteria were the symptoms of FOH. To this
list they added several more CBQ items that demonstrated particular
importance during the dimensional analysis. The resulting list of 22
CBQ symptoms is called the Core Phenotype. It is, in their minds, a
more accurate list of symptom criteria by which to identify a child at
risk for bipolar disorder. (For the full article, click here.)
A program on the JBRF website provides scoring of the CBQ that will
indicate whether or not a child matches a Core phenotype definition of
the illness. (to get to the CBQ and its scoring, click here.)
The next step the investigators took was to determine the
heritability of the FOH index, the ten CBQ dimensions and the proposed
Core phenotype. Determining heritability is very important as it
establishes that the characteristic or symptom under question is
inherent to the illness (and thus genetically relevant) rather than
brought about through cultural or environmental influences. The results
of this inquiry provided investigators with much confidence that they
were traveling down a fruitful path.
The studies showed that FOH is indeed a highly heritable feature
likely rooted in a genetic source. Analysis of the 10 different CBQ
factors sorted them into an order of relative heritable importance to
the phenotype. The factor that proved to have far and away the greatest
concordance, significantly higher than either mania or depression, was
the one which linked anxiety or fearfulness with aggression. And the
Core phenotype, as a composite of 22 CBQ symptoms, inclusive of FOH,
was also found to describe a highly heritable profile. Clearly,
investigators were on solid ground to consider FOH as the basis for a
genetically identifiable subtype of the disorder. (For the full
article, click here.)
To learn more about the FOH phenotype investigators hypothesized
that as the measure of FOH increased, so too would the severity of
selective factors, including mania and depression, and various course
of illness factors such as age of onset, hospitalization, school
difficulty and involvement with the juvenile justice system. To do
this, they first divided a large group of children with a standard
diagnosis of bipolar disorder into three groups depending upon their
measure of FOH; none, low or high. As it happens, roughly one third of
the children fell into each group.
Children who fit the highFOH group experienced a significantly
greater frequency of manic and depressive symptoms than the other
children. Investigators found that the total number of endorsed CBQ
items increased significantly as measures of FOH increased. They also
determined that, while all three groups experience significant severity
of illness measures, the FOH children experience significantly more
frequent hospitalizations and increased incidence of school failure.
Having established the clinical importance of this subgroup of
children, investigators performed another dimensional analysis to
determine the symptom-clusters most highly associated with, and
predictive of, the FOH trait feature. The new analysis grouped together
ten slightly different symptom-clusters than the previous CBQ factor
analysis. Taken together, these factors provide a rather complete sense
of the experience imposed by this subtype of the illness. The factors
were given the dimensional names of territorial aggression,
attention/executive function, mania, harm to self/others, self-esteem,
sleep, sensory, hypersexuality, PPSO (a combined factor consisting of
psychosis, parasomnias, sweet cravings and obsessions/germ
contamination fears) and anxiety. Investigators determined that as a
child’s FOH measure increased, from none to low to high, so too did
each one of these factors. But researchers were able to determine that
the following six factors; territorial aggression, harm to self/others,
self-esteem, PPSO, anxiety and Sleep/Arousal, when taken together, are
able to predict 96% of the children who are considered to have the FOH
phenotype. (For the full article, click here.)
To summarize, the work conducted over the past six years has brought
to light a profile of juvenile bipolar disorder that differs
substantially from the current conceptualization. The comprehensive set
of symptoms brought together in this new phenotype points towards
dysregulation of basic homeostatic processes underlying the disorder.
Many of the behaviors can be looked at as responses to threats or
dysregulation of basic survival systems.
To date, the work has defined a highly heritable trait of the
disorder that can serve as the basis for examining a more homogeneous
subgroup of the illness. That subgroup can be easily identified for
both clinical and research purposes and is of great clinical importance
as they are the children who are most severely impacted by the illness.
The work has also resulted in the identification of a potential
biomarker that may provide the basis for confident differential
diagnosis.
What The New Phenotype Leads To
Breaking through conceptual constraints to develop new ways of
thinking about a diagnostic process has been a formidable challenge.
Acceptance of this novel view will require an open-mind.
JBRF sponsored research is now turning to a genome-wide scan in an
effort to track down the genes that cause the susceptibility for the
illness. We are optimistic that the delineation of the FOH phenotype
will make it more likely that the genome-wide study will be successful.
In the meantime, the insights that have resulted from the dimensional
study of the disorder have led investigators to develop some clearer
ideas of the underlying biology of the disorder.
IF YOU WOULD LIKE TO DONATE TO JBRF VIA PAYPAL, PLEASE CLICK HERE.
References
1. Cheng, R., Juo, S.H., Loth, J.E., Nee, J., Iossifov, I.,
Blumenthal, R.,
Sharpe, L., Kanyas, K., Lerer, B., Lilliston, B., Smith, M., Trautman,
K., Gilliam, T.C., Endicott, J., Baron, M., 2006. Genome-wide linkage
scan in a large bipolar disorder sample from the National Institute of
Mental Health genetics initiative suggests putative loci for bipolar
disorder, psychosis, suicide, and panic disorder. Mol. Psychiatry 11,
252–260.
2. Mataix-Cols, D., Wooderson, S., Lawrence, N., Brammer, M.J.,
Speckens, A., Phillips, M.L., 2004. Distinct neural correlates of
washing, checking, and hoarding symptom dimensions in
obsessive–compulsive disorder. Arch. Gen. Psychiatry 61, 564–576.
Mataix-Cols, D., Rosario-Campos, M.C., Leckman, J.F., 2005. A
multidimensional model of obsessive–compulsive disorder. Am. J.
Psychiatry 162, 228–238.
Mataix-Cols, D., Pertusa, A., Leckman, J.A., 2007. Issues for DSM-V:
how should obsessive–compulsive and related disorders be classified?
Am. J. Psychiatry 164, 1313–1314.
Mataix-Cols, D.,Nakatani, E.,Micali,N.,Heyman, I., 2008. Structure
of obsessive– compulsive symptoms in pediatric OCD. J. Am. Acad. Child
Adolesc. Psych. 47, 773–778.
New: Are you interested in finding
out if your children qualify to participate in the JBRF's research studies?
Learn more here.
Research Studies
Context and Summary of JBRF Sponsored Research
Clinical Phenomenological
Study of Childhood-onset Bipolar Disorder
Validation Study of
The Child Bipolar Questionnaire V.2
Circadian Rhythm - Sleep/Wake
Study in Juvenile-onset Bipolar Disorder
Neuropsychological Testing
in Juvenile-onset Bipolar Disorder
Affected Sibling Pair
www.kristen-mcclure-therapist.com This is really interesting. Previously we were only to consider, traditional signs of mania as evidence of the diagnosis, now they are suggesting in YOUNG Children, there is a rare irritable only mania
www.sciencedaily.com
ScienceDaily (June 25, 2009) A new study from Bradley Hospital and The Warren Alpert Medical School of Brown University, as well as two other institutions, adds to mounting evidence that clinicians consider irritability as a symptom when diagnosing pediatric bipolar disorder.
Mental Health Advocacy | North Carolina Mental Hope | Creating Public Awareness of Mental Health Iss
ncmentalhope.org
North Carolina Mental Hope seeks to increase public awareness of mental health issues, erase the stigma of mental illness, empower mental health consumers and family members and give them a greater voice in state policymaking through the effective use of communications media.
Jackie www.kristen-mcclure-therapist.com: Excellent information in the newsletters section which are "short reads". The book is a must have!
www.bipolarchild.com
Resources for Children with Pediatric Bipolar Disorder and their families. DVD '24' chronicles a day in the life of a family dealing with early-onset bipolar disorder. The Bipolar Child is the acclaimed ...
Jackie www.kristen-mcclure-therapist.com: In addition to Wright's Law this is another resource that parents with children that have any type of mental or physical disability cannot live without. They are truly a blessing.
www.cfcrights.org
We believe that every child is unique and, therefore, more multi-faceted than merely a bundle of actions or behaviors. Actions and behaviors, regardless of what type, point to issues of wholeness – physical, emotional, intellectual, and have repercussions. ...